There has been a need for new anticancer and antifungal compounds. It has been previously determined that a number of 5-amino-1-aryl-1-penten-3-one hydrohalides and related compounds possess significant cytotoxic and anticancer properties. These previously synthesized compounds were developed as thiol alkylators since unsaturated ketones have a marked affinity for thiols in contrast to amino and hydroxy groups. Hence, interactions with nucleic acids may be avoided and the disadvantages of certain alkylating agents such as mutagenicity and carcinogenicity may be absent. Support for the contention that these compounds have a different mode of action than such widely used alkylating agents as melphalan was provided by noting their displaying similar cytotoxicity towards melphalan-resistant and melphalan-sensitive neoplastic cells i.e. the melphalan-resistant cell lines were free from cross resistance to these Mannich bases. In addition, several series of Mannich bases have been prepared recently which were designed using the concept of sequential cytoxicity. This theory may be defined as the successive release of two or more cytotoxic agents whereby greater toxicity to malignant rather than normal cells will be displayed.
As a mechanism for cell death, apoptosis plays an important role in the regulation of normal and cancer cells. The characteristic features of apoptosis which distinguish it from necrosis are cell shrinkage, cytoplasimic blebbing, loss of membrane architecture, chromatin condensation, fragmentation of DNA into oligonucleoside-sized fragments (180-200 bp in length) and formation of apoptotic bodies. Endogenous cleavage of the DNA is believed to be carried out by an endogenous Ca.sup.2+ /Mg.sup.2+ dependent endonuclease that can be inhibited by the addition of Zn.sup.2+. Inhibitors of messenger RNA and protein synthesis in many cases have been reported to suppress apoptosis. Apoptosis is considered to be the major mechanism by which antineoplastic drugs mediate their cytotoxic effects. Moreover tumor sensitivity and resistance to drugs has also been linked, at least in part, to inactivation of a genetic program for cell death. Induction of apoptosis in cancerous cells may therefore be an effective approach for the treatment of cancer. It is an object of this invention to provide a compound capable of inducing apoptosis in cancerous cells.
As indicated above, there is also a need for novel antifungal agents with different chemical structures and targets of action from the drugs used today. In this manner, new therapies can evolve which not only exert significant antifungal properties but can be employed in cases where drug resistance has emerged.
Recently, Mannich bases of a series of acyclic conjugated styryl ketones were synthesized which possessed minimum inhibitory concentrations (MICs) in the 0.1-1.5 mM range against pathogenic yeasts, in particular Candida albicans. However, the potencies of these novel compounds towards C. albicans were approximately 2-3 orders of magnitude lower than that of the established antifungal drugs such as fluconazole and amphotericin B which had mean MIC values of approximately 0.8 .mu.m and 0.6 .mu.m, respectively. Since the compounds previously studied contained only one center for nucleophilic attack by cellular thiols, there has been a need for a series of new conjugated styryl ketones which possessed an additional site at which thiol-alkylation could occur wherein the chemical reactivity of the two centres for nucleophilic attack would be predicted to be different and alkylation of cellular thiols would proceed in a stepwise fashion. Thus it is a further object of the invention to provide antifungal compounds of increased potencies.